Murine double nullizygotes of the angiotensin type 1A and 1B receptor genes duplicate severe abnormal phenotypes of angiotensinogen nullizygotes.
Rodents are the unique species carrying duplicated angiotensin (Ang) type 1 (AT1) receptor genes, Agtr1a and Agtr1b. After separately generating Agtr1a and Agtr1b null mutant mice by gene targeting, we produced double mutant mice homozygous for both Agtr1a and Agtr1b null mutation (Agtr1a-/-; Agtr1b-/-) by mating the single gene mutants. Agtr1a-/-, Agtr1b-/- mice are characterized by normal in utero survival but decreased ex utero survival rate. After birth they are characterized by low body weight gain, marked hypotension, and abnormal kidney morphology including delayed maturity in glomerular growth, hypoplastic papilla, and renal arterial hypertrophy. These abnormal phenotypes are quantitatively similar to those found in mutant mice homozygous for the angiotensinogen gene (Agt-/-), indicating that major biological functions of endogenous Ang elucidated by the abnormal phenotypes of Agt-/- are mediated by the AT1 receptors. Infusion of Ang II, AT1 blockers, or an AT2 blocker was without effect on blood pressure in Agtr1a-/-; Agtr1b-/- mice, indicating that AT2 receptor does not exert acute depressor effects in these mice lacking AT1 receptors. Also, unlike Agt-/- mice, some Agtr1a-/-; Agtr1b-/- mice have a large ventricular septum defect, suggesting that another receptor such as AT2 is functionally activated in Agtr1a-/-, Agtr1b-/- mice.
Tsuchida
S
S
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2584, USA.
Matsusaka
T
T
Chen
X
X
Okubo
S
S
Niimura
F
F
Nishimura
H
H
Fogo
A
A
Utsunomiya
H
H
Inagami
T
T
Ichikawa
I
I
D000311:Adrenal Glands / Q000187:drug effects / Q000473:pathology; D000777:Anesthetics / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure; D007093:Imidazoles / Q000494:pharmacology; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D010641:Phenotype; D011725:Pyridines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism*; D012504:Saralasin / Q000494:pharmacology; D013194:Staining and Labeling; D013777:Tetrazoles / Q000494:pharmacology; D013874:Thiopental / Q000031:analogs & derivatives / Q000494:pharmacology; D015053:Zygote; D001616:beta-Galactosidase / Q000032:analysis
D000777:Anesthetics; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000808:Angiotensinogen; D000804:Angiotensin II; C073402:PD 123319; C004316:thiobutabarbital; D001616:beta-Galactosidase; D012504:Saralasin; D013874:Thiopental; D019808:Losartan; C081643:candesartan